Device and method of neuromodulation to effect a functionally restorative adaption of the neuromuscular system

ABSTRACT

Described herein are methods and systems for improving or adapting a breathing pattern of a patient with disordered breathing toward a more helpful state, as well as systems and devices for adapting breathing. These methods and systems may be used for improving sleep in patients with sleep disordered breathing and a system by which to implement devices for performing these methods.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application is a divisional of U.S. patent application Ser.No. 12/690,410, filed on Jan. 20, 2010, titled “DEVICE AND METHOD OFNEUROMODULATION TO EFFECT A FUNCTIONALLY RESTORATIVE ADAPTION OF THENEUROMUSCULAR SYSTEM,” now U.S. Patent Publication No. 2010-0198296-A1,which claims priority to U.S. Provisional Patent Application No.61/145,935, titled “DEVICE AND METHOD OF NEUROMODULATION TO EFFECT AFUNCTIONALLY RESTORATIVE ADAPTATION OF NEUROMUSCULAR SYSTEM” filed onJan. 20, 2009, each of which is herein incorporated by reference in itsentirety.

U.S. patent application Ser. No. 12/690,410 is also aContinuation-in-Part of U.S. patent application Ser. No. 12/261,979,titled “METHOD OF IMPROVING SLEEP DISORDERED BREATHING” filed Oct. 30,2008, now U.S. Patent Publication No. 2009-0118785-A1, which claimspriority to U.S. Provisional Patent Application No. 60/983,915 “METHODOF IMPROVING SLEEP DISORDERED BREATHING” filed on Oct. 30, 2007, each ofwhich is herein incorporated by reference in its entirety.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference in their entirety and to the sameextent as if each individual publication or patent application werespecifically, individually, and explicitly incorporated by reference intheir entirety.

FIELD

The invention relates to apparatus and methods for improving the qualityof sleep in patients who have or are at risk of having sleep-disorderedbreathing. In particular, the apparatus and methods described hereinrelate to treatment of patients with disorders impacting upper motorneurons, including those with amyotrophic lateral sclerosis (ALS) andcentral sleep apnea. The invention also relates to systems and methodsfor treating malfunctioning neuromuscular pathways through theapplication of neurostimulation to cause a reflexive or automaticfunctional outcome. One embodiment is a treatment for sleep disorderedbreathing, and more particularly a therapeutic restoration or adaptiveregaining of breathing ability through neuromodulation orneurostimulation to a more healthful state wherein the need for otherforms of breath-supportive therapy is diminished or eliminated.

BACKGROUND

Patients with neuromuscular diseases such as amyotrophic lateralsclerosis often suffer from central nervous system-mediated sleepdisorders that can cause orthopnea, nocturnal hypoventilation, and areduction in REM sleep. Noninvasive positive pressure ventilation(NIPPV) therapy in the form of with bi-level positive airway pressure(BiPAP) or continuous positive airway pressure CPAP) is commonlyprovided to these patients, with some success, in an effort to restoresleep toward normal. Further, NIPPV therapy has been shown to increasesurvival times of ALS patients. However, a significant percentage ofpatients do not tolerate the positive pressure intervention well, atleast in part because of bulbar symptoms, such as difficulty withmanagement of swallowing, saliva, aspiration, and communication, orother coping issues. Other therapeutic approaches to improving thequality of sleep in patients with neuromuscular diseases and associatedcentral nervous system mediated disorders of sleep are desirable.

The therapeutic use of neuromodulation or neurostimulation in order tocreate a change in nerve conduction or muscle function at the site suchmodulation or stimulation has met with some success in varioustherapeutic circumstances. For example, periodic stimulation by spinalcord stimulators has been used to block pain sensation, periodicstimulation by deep brain stimulation (DBS) methodology has been used toblock tremors, functional electrical stimulation (FES) has been able tocreate movement, periodic stimulation by vagus nerve stimulation (VNS)methodology has been able to block epileptic seizures, and intermittentstimulation by VNS has been shown to block hunger signals and create asensation of satiety.

It would be desirable to have neuromodulatory or neurostimulatorytherapeutic modalities available that would encourage a functionallybeneficial outcome by introducing reflexive or automatic pathways thatwould work in conjunction with the applied therapy. This could beapplied, for example, to conditions that compromise breathingparticularly as it occurs during sleep, as in sleep apnea.

SUMMARY OF THE DISCLOSURE

The invention provided herein includes methods of improving or adaptinga breathing pattern of a patient with disordered breathing toward a morehelpful state, as well as systems and devices for adapting breathing. Insome variations, described herein are methods and systems for improvingsleep in patients with sleep disordered breathing and a system by whichto implement devices for performing these methods.

For example, a method for adapting a breathing pattern of a patient withdisordered breathing toward a more healthful state may include:implanting a neurostimulatory device in the diaphragm of the patient;stimulating the diaphragm; evaluating the patient's diaphragm byelectromyographic (EMG) methodology to determine the effectiveness ofthe establishment of an automatic, reflexive, or synchronized breathingmechanism. The method may also include the step of evaluating thepatient by polysomnographic (PSG) methodology to assess diminishment ofsleep disordered breathing.

Also described herein are methods to entrain breathing comprisingrepetitively applying low-levels of physiologically normal stimulationto establish a baseline automatic function.

For example, described herein are methods of restoring a compromisedneurophysiological function comprising: applying electrical stimulationto a compromised target; displacing a maladapted physiologicalfunctioning; and establishing an appropriately coordinated function in atarget and reflex pathway.

Also described herein are systems for adapting breathing of a patientwith sleep-disordered breathing toward a more healthful state. Thesystem may include: a neurostimulation device, the device including astimulator and electrodes configured to be implanted and interface witha stimulated end target; an electromyographic activity monitorconfigured to display and/or process data from the electrodes; and aprogramming device to implement changes in levels and periodicity ofapplied signals based on electromyographic activity and functional need.

In some variations, the methods and devices described herein may be usedduring or for sleep. For example, described herein are systems forimproving breathing (and/or sleep) in a patient with centrally-mediatedsleep disordered breathing may include an electronic signal generator,one or more electrodes operably connected to the signal generator, theone or more electrodes configured to stimulate a diaphragm, anelectromyographic (EMG) processor arranged to capture EMG activity dataof the diaphragm while being paced by the one or more electrodes, and asleep sequencer configured to integrate any combination of stimulationparameter input, respiratory parameter input, and EMG data, and toconvey processed data from these inputs to the electronic signalgenerator. Embodiments of the electronic signal generator typicallyinclude a power supply, an impedance detector, a microcontroller, awaveform generator, and one or more signal drivers. In some embodiments,the EMG processor is configured to convey data to a display; inembodiments the EMG processor is configured to convey data to the sleepsequencer; in some embodiments, the EMG processor is configured toconvey data both to a display and the sleep sequencer.

In some embodiments, the sleep sequencer is further configured to rampup stimulus intensity to a threshold level. The sleep sequencer may bevariously configured such that, for example, the stimulus intensity rampup provides an increase in pulse duration followed by an increase inpulse amplitude, the stimulus intensity ramp up provides an increase inpulse amplitude followed by an increase in pulse duration, or theintensity ramp up may provide an interleaved increase in pulse amplitudeand pulse duration. The sleep sequences may also be configured toprovide a stimulus ramp up with various envelope forms; for example, thestimulus ramp may have a linear envelope, an exponential envelope, or itmay have an arbitrarily-shaped envelope.

A method of improving sleep in a patient by using a system as summarizedabove, with one or more electrodes implanted in the diaphragm forstimulation of the diaphragm, may include adapting stimulationparameters to support respiration during sleep, and stimulating thediaphragm in a therapeutic regimen with the one or more electrodes tosupport respiration after the onset of sleep, the regimen including theadapted stimulation parameters. The stimulation typically operatesindependently of any voluntary respiratory effort of the patient ordetection of such effort in terms of feedback from the diaphragm.

The method is therapeutically appropriate for various types of patients,thus prior to the adapting and stimulating steps, the method may includediagnosing a patient as having a neuromuscular disease, particularlythose with a disorder impacting upper motor neurons, such as, forexample, amyotrophic lateral sclerosis (ALS) and central sleep apnea.More generally, the method may include (prior to the adapting andstimulating steps) identifying the patient as being at risk for sleepdisordered breathing. Such patents may be, for example, an ICU patientor a post-surgical patient. More particularly, a post-surgical patientat risk may be one who has undergone a bariatric procedure, as bariatricpatients are already commonly at risk for sleep disordered breathing.Another general class of patients at risk for sleep disordered breathingincludes any patient having an upper motor neuron dysfunction thatresults in temporary or permanent diaphragm paralysis.

The method as summarized above, prior to the adapting and stimulatingsteps, includes a procedure whereby one or more electrodes are implantedin the diaphragm of the patient. These electrodes are used during theadapting phase of the method, as summarized below, and in a therapeuticregimen that follows the adapting phase.

Continuing more specifically with the aspect of the method that involvespatient selection, the method may include diagnosing the patient ashaving sleep-disordered breathing by any one or more criteria includingmorning headaches, daytime sleepiness, PSG recordings consistent withdisordered sleep, diaphragm EMG recordings during sleep consistent withdisordered sleep, or pulmonary function testing data consistent withdisordered sleep. Further, in the event that sleep-disordered breathingis found, the method includes diagnosing the patient's sleepsleep-disordered breathing as being centrally-mediated.

With regard to the parameter-adapting aspect of the method, whereinparticular values for stimulation parameters to support respirationduring sleep are determined, the method may include determining any oneor more of an appropriate time interval after the onset of sleep tolapse prior to initiating stimulation, a threshold level of stimulationsufficiently low so as to allow onset of sleep, a threshold level ofstimulation sufficient to stimulate diaphragm contraction, or athreshold level sufficient to support breathing during sleep. By thisaspect of the method, the therapeutic regimen can be tailored to thephysiological status of the patient.

Embodiments of the method may further include monitoring the EMG of thepatient during the therapeutic regimen. And in some embodiments of themethod, stimulating the diaphragm to support respiration includesinitiating a breath and supporting a breath to completion.

After implementing the therapeutic regimen, the method may furtherinclude evaluating the patient again for presence of sleep disorderedbreathing by any one or more same diagnostic criteria as above (i.e.,morning headaches, daytime sleepiness, PSG recordings consistent withdisordered sleep, diaphragm EMG recordings during sleep consistent withdisordered sleep, or pulmonary function test data consistent withdisordered sleep) in order to know whether the therapy has beeneffective or if a revision of the patient-specific parameters isindicated. Accordingly, in the event of a finding of continued presenceof sleep-disordered breathing, the method may further include revisingthe adapted stimulation parameters, and implementing a revisedtherapeutic regimen for the patient based on the revised parameters, theregimen comprising stimulating the diaphragm with the one or moreelectrodes to support respiration.

With further regard to the stimulating step of the method, stimulatingthe diaphragm in a therapeutic regimen after the onset of sleeptypically includes waiting for a period of time after the onset of sleepbefore initiating stimulation. Determining the appropriate wait timeafter onset of sleep to initiate diaphragm stimulation may includedetermining the onset of sleep by monitoring the level of one or morephysiological parameters and determining when they fall below athreshold value, the parameters including any of the diaphragm EMG, anEEG, or body movement. Still further with regard to the stimulatingstep, stimulating the diaphragm in a therapeutic regimen includesgradually ramping the stimulation over time to a reach a steady statelevel of stimulation, as will be summarized in further detail below.

In another aspect of the invention, a method of improving sleep in apatient with sleep-disordered breathing or at risk thereof includeselectrically stimulating the patient's diaphragm with a sleep-specificstimulation protocol: That stimulation protocol includes initiating asleep onset process, ramping the stimulation to a first level that doesnot exceed a level at which sleep onset is interrupted, (the patient)initiating sleep, synchronizing a natural sleep respiratory rate with arate supported by the stimulation while ramping stimulation to a secondlevel which is sufficient to provide detectable diaphragm contraction,and ramping the stimulation to a third level which is sufficient tosupport breathing during sleep.

Ramping the electrical stimulation of the diaphragm, as it occurs inthese various phases of the therapeutic method, to varying levels atvarious steps, may include increasing pulse duration and then increasingpulse amplitude, increasing pulse amplitude and then increasing pulseduration, or increasing pulse amplitude and pulse duration in aninterleaved manner. With regard to the general form of the ramping,ramping may occur with a linear envelope, with an exponential envelope,or with an envelope of an arbitrary or irregular shape.

Prior to the electrically-stimulating step, the method may includedetermining any one or more of an appropriate time interval after theonset of sleep to lapse prior to initiating stimulation, a thresholdlevel of stimulation sufficiently low so as to allow onset of sleep, athreshold level of stimulation sufficient to stimulate diaphragmcontraction, or a threshold level sufficient to support breathing duringsleep.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A provides a simplified block diagram of one variation of a methodfor treating disordered breathing as described herein.

FIG. 1B provides an overview and further detail of a method of improvingsleep-disordered breathing.

FIG. 2A provides a simplified block diagram of a system for implementingthe method.

FIG. 2B provides an overview and further detail of a system forimplementing the method.

FIGS. 3A and 3B provide EMG charts of the breathing of a conscious(awake) ALS patient who had been implanted with DPS electrodes 18 monthsprior to these EMG readings. FIG. 3A shows normal awake breathing; FIG.3B shows maximal breathing.

FIGS. 4A and 4B provide two EMG charts showing sleep breathing of an ALSpatient with sleep disordered breathing. FIG. 4A shows a Cheyne-Stokestype breathing pattern. FIG. 4B shows an EMG chart of the ALS patientbreathing with and without diaphragm pacing ((DPS) support.

FIGS. 5A and 5B show EMG charts of an ALS patient showing an improvementin burst activity over the course of 11 weeks of DPS therapy. FIG. 5Ashows an EMG chart recorded at the outset of the therapy. FIG. 5B showsan EMG chart recorded after 11 weeks of DPS therapy.

FIG. 6 shows a normal EMG of a right diaphragm of a patient that issynchronizing with the electrically-paced left diaphragm.

FIG. 7 shows the EMG of a patient prior to diaphragm pacing stimulationtherapy able to hold her breath, with no visualized diaphragm EMG. Thispatient may have central sleep dysfunction and may be still early in thedisease course.

FIG. 8 shows the EMG of a patient (advanced in her ALS course) who hasbeen treated with diaphragm pacing, and now has a rhythmic breathingpattern, but can no longer stop her breath, and thus shows breakthroughbreathing.

FIG. 9 provides a closer view of a five-second visualization of the samepatient of FIG. 8, showing that the amount of diaphragm and perhaps themotor neurons that are involved in this breathing are different thanduring voluntary breathing.

DETAILED DESCRIPTION

Described herein are methods and devices for applying neurostimulationand/or neuromodulation to increase the ability of abreathing-compromised patient to breathe independently or moreindependently. The inventors have observed that, for example, when onehemi-diaphragm of a spinal cord (SC)-injured patient is stimulated,electromyographic activity may be elicited on the contralateralhemi-diaphragm. Further, when the diaphragm of a spinal cord-injuredpatient was stimulated, accessory muscles were also reflexivelycontracted. In ALS patients, treatment with diaphragm pacing stimulationmay result in a gradual but ultimately marked adaptation of voluntarybreathing. The initial application of diaphragm stimulation is typicallyunsynchronized with voluntary breathing and causes discomfort for thepatient. Following several sessions of stimulation, however, thevoluntary breathing may become time-synchronized with the diaphragmstimulation. This observation provided an early insight into theinventive concept of an automatic or reflexive function induced by thestimulation which is described herein.

The inventors have also observed that ALS patients can hold (inhibit)their breath (as can normal subjects) to a point where the volitionalholding of breath is overridden, i.e., a disinhibition that stopsbreath-holding and allows breathing to continue. After a period ofdiaphragm pacing stimulation (DPS) training, however, one particular ALSpatient (initially able to hold her breath) was unable to hold herbreath at all (i.e., demonstrating a disinhibition of breath-holdingability). This observation suggested that a baseline automatic functionhad been established that moved into the physiological vacuum associatedwith the lost central communication from the respiratory centers.

The observations described above are illustrated in the EMG traces ofFIGS. 6-9. FIG. 6 provides a 30-second view a normal EMG of a rightdiaphragm that is synchronizing with an electrically-paced leftdiaphragm. Pacing artifacts are evident in the EMG trace of the rightdiaphragm. These data are consistent with an afferent effect originatingin the left diaphragm that is manifesting in contralateral accessorymuscles. FIG. 7 provides a 30-second view of the EMG of a patient whohas not yet received diaphragm pacing stimulation therapy who is able tohold her breath, with no visualized diaphragm EMG. This patient may havecentral sleep dysfunction and may be still early in the disease course.FIG. 8 provides a 30-second view of the EMG of a patient (advanced inher ALS course) who has been subjected to diaphragm pacing, and now hasa rhythmic breathing pattern, but can no longer stop her breath, andthus shows breakthrough breathing. FIG. 9 provides a closer view of afive-second visualization of the same patient of FIG. 8, showing thatthe amount of diaphragm and perhaps the motor neurons that are involvedin this breathing are different than during voluntary breathing.

Such data lead to and supports the inventive concept that naturalphysiological support (e.g., through the application ofneurostimulation) to a functional physiological element (such as thediaphragm) can affect a larger physiological system (such asrespiration) by eliciting centrally mediated automatic function (inconjunction with or autonomous from the applied therapy) and reflexivefunction that supports the applied therapy.

The invention described herein thus provides embodiments of a system andmethods that make use of neuromodulation in the form of diaphragmstimulation to effect an adaptation of the neural and muscularcomponents of breathing in breathing-compromised patients. Thisadaptation allows a greater degree of independent (autonomous,automatic, or naturally-supported and sustained) breathing. Thedevelopment of such naturally-supported sustained breathing is amanifestation of neurologically adaptive process and the establishmentof a more healthful state for the patient.

Embodiments of the system include a neurostimulatory device, whichincludes a stimulator and electrodes that interface (i.e., provide anartificial synapse) with the stimulated end target in the diaphragm; anelectromyographic activity monitor that records and displays informationthrough the implanted electrodes from the end target; and a programmingdevice or controller to implement changes in levels and periodicity ofapplied signals based on electromyographic activity and functional need.In various embodiments, each of the enumerated components of the systemmay be controlled and operated independently of the other components.Embodiments of the neurostimulatory system may be applied towardtreatment of both central sleep apnea and complex sleep apnea.

For example, when treating a patient with presumptive central sleepapnea, the therapeutic method may include the following steps:

First (1): Evaluating the patient by polysomnographic (PSG) methodologyin order to diagnose the cause of sleep disordered breathing in apatient, and determining it to be central sleep apnea.

Second (2): Implanting a neurostimulatory device in the diaphragm of thepatient.

Third (3): Stimulating the diaphragm with the device at a level either(3a) below the patient's movement or sensory threshold, or (3b or 3c)above the patient's movement or sensory threshold. Step (3a) involves:Stimulating the diaphragm at a level below movement/sensory threshold tocreate an automatic baseline pacing through reflex/afferent effects onthe central respiratory drive centers. Step (3b) includes: Stimulatingthe diaphragm at a level above the movement or sensory threshold tosupport a diaphragm movement that is sufficient to ventilate the patientbut remains comfortably tolerated. The initial sessions may occur whilethe patient is awake in order to provide adaptation of voluntary orintrinsic respiration with open loop stimulation. Once adaptationoccurs, the patient typically sleeps with the device on throughout thenight. The facilitation of the onset of sleep may occur byimplementation of methods described in greater detail below. Step (3c)includes: Stimulating the diaphragm at a level above the movement orsensory threshold to create movement that is sufficient to ventilatepatient but is also comfortably tolerated for the duration of 30 minutesessions. The diaphragm of the patient then conditions throughelectrode-stimulated exercise while the patient is awake to create anautomatic breathing mechanism, this representing a disinhibition of theability to hold a breath. This aspect of the method may require a“breakthrough breathing refresher” prior to sleep.

Fourth (4): Re-evaluating the patient by polysomnographic (PSG)methodology to assess diminishment or elimination of central sleepapnea.

Fifth (5): Evaluating the patient's diaphragm by electromyographic (EMG)methodology to determine the effectiveness of the establishment of anautomatic breathing mechanism.

The steps of the above described method, particularly with regard to thesimulating protocol, may vary depending on particulars of the centralapnea, which may be due to ALS, non-hypercapnic, hypercapnic, or ofcongenital origin.

When treating a patient with a presumptive complex sleep apnea, thetherapeutic method may include the following steps:

1. Evaluating the patient by polysomnographic (PSG) methodology in orderto diagnose the cause of sleep disordered breathing in a patient, anddetermining it to be a complex sleep apnea, distinct from central sleepapnea.

2. Implanting a neurostimulatory device in the diaphragm of the patient.

3. Stimulating the diaphragm with the device at a level either below orabove the patient's movement or sensory threshold.

4. Re-evaluating the patient's diaphragm by polysomnographic (PSG)methodology to assess diminishment or elimination of complex sleepapnea.

5. Evaluating the patient's diaphragm by electromyographic (EMG)methodology during obstructive episodes.

6. Applying continuous positive airway pressure (CPAP) therapy toeliminate obstructions as needed.

7. Increasing stimulation to increase upper airway pressure (asmeasured, for example, with maximal inspiratory pressure (MIP) duringstimulation to level need to improve patency of airway opening.

8. Titrating CPAP, to diminish or eliminate necessity thereof, based onextent of obstructive apneic events.

9. Evaluating the patient's apneic status after stabilizing the finalCPAP settings.

The neurophysiological adaption of the respiratory system, as describedabove in the context of improving the breathing of patients with sleepcompromised breathing due to centrally-mediated apnea or complex apnea,has other therapeutic applications as well. One example is provided bythe therapeutic adaptation of patients with daytime hypoventilation.Repetitive nighttime diaphragm pacing stimulation may be able to entrainautomatic breathing that would otherwise slow during a daytime sleepperiod. Another example is provided by the plight of hospitalized illpatients who suffer temporarily compromised breathing. Patients who areill due to a wide variety of conditions, but particularly those who havesuffered respiratory arrest, are subject to temporarily compromisedrespiration and are often intubated at night due to insufficientrespiration during sleep. Without such respiratory support patients,particularly elderly patients, can die. The neurostimulatory adaptivetherapy described herein would be of considerable benefit to suchpatients.

The application of physiologically natural stimulation by way ofelectrodes may therefore induce the development of reflexive pathways inassociation with the stimulation, and thus have immediate (or lessimmediate) effects, which may be long-lasting. In the context ofrespiration, as described herein, accessory muscles working with thediaphragm through spinal reflex pathways or muscles controlling upperairway patency through central spinal sensory and/or reflex paths may beinduced by the applied stimulation. It is also possible that some degreeof neuroplastic recovery may contribute to functional recovery, but thedevelopment of physiologically appropriate reflexive pathways isconsidered the more likely basis by which the therapeutic method iseffective.

The methods described herein can be broadly understood as a therapeuticintervention that provides neurological, or neuromuscular stimulation ormodulation of a compromised and dysfunctional neuromuscular target, andby such stimulation, including variable periodicity, and varying periodof rest between periods of stimulation, function is improved orrestored. The inventive method and system are described in theparticular context of disordered breathing and diaphragmatic function.The system and methods described herein may also be generally applied toother anatomical sites and their respective neuromuscular functionality,such as for example, the lower esophageal sphincter, which whencompromised, can contribute to gastroesophageal reflux disease (GERD).

Also described herein are systems and methods of diaphragm pacingstimulation for the treatment of disordered sleep, including thetreatment of disordered sleep (e.g., apnea) in patients withneuromuscular diseases such as amyotrophic lateral sclerosis (ALS).Embodiments of the invention may also be usefully applied to patientswith neuromuscular diseases other than ALS who experience centralnervous system-mediated sleep disordered breathing. Embodiments of theinvention may also be applied as therapy for patients with sleepdisordered breathing due to other forms of sleep pathology, includingthose not-mediated by the central nervous system, such as obstructive ormixed (complex) apnea. Further, embodiments of the invention may beapplied to patients who are considered to be temporarily at risk ofrespiratory compromise or failure, as for example, would be associatedwith surgery, anesthesia, or during the period of post-operativerecovery with diaphragm activity monitored by clinical personnel. Someembodiments of the invention may be applied to the support of sleep inpatients in a chronic manner, such as patients with a neuromusculardisease, in which embodiments electrodes adapted for long-term orpermanent residence may be used. Other embodiments of the invention maybe applied to patients that are in temporary need of respiratorysurveillance or support, such as surgical patients, in which embodimentselectrodes adapted for temporary placement may be used.

Improving the sleep by implementation of the inventive method can beappreciated by the patient in subjective terms, as well as measurable inobjective terms. For example, improving sleep may include increasingtotal sleep time per night and/or increasing total REM sleep time pernight. In some of the embodiments whereby REM sleep time is increased,the method further includes alleviating severity of or preventingdevelopment of intensive care unit psychosis. In other embodiments,improving sleep includes decreasing the level of sleep disturbance, suchdisturbances including, for example, periods of restlessness orwakefulness. In still other embodiments, improving sleep includessupporting a regular breathing rate during sleep. In some embodiments inwhich a regular breathing rate is instilled in the patient, the regularbreathing rate prevents the development of central hypoventilationsyndrome (CHS), or alleviates the severity thereof. In addition to thesevarious relatively immediate undesirable consequences of disturbedsleep, sleep disturbance can contribute to many other adverse outcomes,such as cardiovascular disease and hypertension, can accrue over thelonger term.

Aspects of the system and method as applied to diaphragm conditioningand acute support for respiratory-compromised patients have beendescribed in U.S. patent application Ser. No. 10/897,685, filed on Jul.23, 2004, which was published as U.S. Pub. No. 2005/0021102 on Jan. 27,2005, now U.S. Pat. No. 7,840,270, which issued on Nov. 23, 2010 and inU.S. patent application Ser. No. 11/716,459, filed on Mar. 9, 2007, nowU.S. Pat. No. 7,962,215, which issued on Jun. 14, 2011.

Returning now to FIGS. 1A-5 b, an overview of the open loop method isprovided in FIGS. 1A and 1B. FIG. 1A is a simplified flow diagram whichoutlines the method in terms of five phases (201-205), which areoutlined in greater detail in FIG. 1B, including 12 steps. A preparatoryaspect of the method 201 includes implanting diaphragm pacing electrodesin a patient. This is Step 1, as shown in FIG. 1B, and is detailed infurther description below. In a preliminary aspect of the method 202,patient-specific stimulatory parameter values are determined in a seriesof Steps 5-7, as shown in FIG. 1B. A sleep-based therapeutic regimenthat improves sleep-disordered breathing starts with an initial part 203of a therapeutic regimen that occurs after a patient has made a decisionto go to sleep, or after the patient has been observed to be in theearly stages of falling asleep. This phase occurs in Steps 5-7, as shownin FIG. 1B. During this phase 203, stimulation is ramped up to astimulatory threshold that was determined during the adapting phase 202of the method. In a second part of the therapeutic regimen 204, whichoccurs after the onset of sleep, stimulation is ramped up to a movementthreshold, as determined during the adapting phase 202 of the method.This phase 204 occurs over the course of Steps 8-11, as shown in FIG.1B. In a third part of the therapeutic regimen 205, sleep is ongoing andsteady and stimulation is being delivered at a steady state, asrepresented by Step 12 as shown in FIG. 1B.

FIG. 1B provides a more detailed view of the method, with individualsteps included. Implantation of diaphragm pacing electrodes (Step 1) maybe by way any of various conventional approaches, such as throughlaparoscopic approaches, a thoracic surgical approach, or by way ofnatural orifice transluminal endoscopic surgery (NOTES). Step 1 is apreparatory procedure, which may take place at a time identified by aphysician, after consulting with the patient, at any reasonable timeprior to initiating a therapeutic regimen. Steps 2-4 relate to aspectsof the method that relate to adapting stimulation parameters to supportrespiration during sleep, such adapted parameters varying frompatient-to-patient, and further, possibly varying with the patient overtime. Steps 5-12 relate to aspects of the implemented regimen, adaptedto the patient particulars as determined in Steps 2-4.

Steps 2-4 of the method (FIG. 1B) relate to aspects of the initialclinical characterization which are performed in a clinic tocharacterize particular physiological aspects of the specific patientprior to formal implementation of a therapeutic regimen. Sensorythreshold (S-thresh) identification (Step 2) is determined byidentifying when patient first senses that stimulus is being applied.This characterization may be done through psychophysical testing orsimply just turning intensity (pulse width/amplitude) until the patientreports that it is being felt. Movement threshold (M-thresh) isidentified (Step 3) as the intensity when the diaphragm movement isvisualized or palpated. Functional threshold identification (Step 4)relates to identifying the stimulation intensity threshold (F-thresh)that elicits inspiration at a level that is sufficient to functionallyventilate the patient during sleep. These steps may all be consideredaspects of the method, as provided by the invention, wherepatient-specific data are collected and then used as input thatdetermines aspects of a therapeutic regimen that are related both to theramp up profile of stimulation and the stead state level of stimulation.

Steps 5-7 of the method (FIG. 1B) relate to a sequence of events thatfollow after the patient turns on the therapeutic device prior to goingto sleep until a time when sleep actually begins. As such, these varioussteps relate to aspects of an initial phase of stimulating the diaphragmin a therapeutic regimen. Step 5 refers to the initiation of events thatoccur immediately after a decision to go to sleep has been made, or as ahealthcare provider observes that patient is preparing to go to sleep,or sleep is inevitable, whether intentionally or not. In Step 6, thestimulus intensity is cyclically ramped up over the duration of apredetermined amount of time to accommodate the sensory perception up toa threshold (determined in Step 2) that is likely to prevent the onsetof sleep. The sleep onset time may be predetermined frompolysomnographic (PSG) studies or set by the patient upon initiation(i.e. an adjustable sleep time). Alternatively, sleep may be detectedthrough a sleep-detection algorithm with the cycle time completing withdetection of sleep. Still further, sleep onset may be noted byobservation of an attending health care professional.

Steps 8-11 (FIG. 1B) of the method relate to steps that occur aftersleep has begun. Once sleep is achieved a sequence of events (Step 8) isinitiated such that the patient synchronizes his or her naturalbreathing to the rate being paced by the electronic signal generator.The stimulus intensity is cyclically ramped up from the sensorythreshold to the movement threshold (Step 9). This signal ramping allowsthe patient's innate breathing to synchronize with the stimulatedbreathing, as such, synchronization is an aspect of the method performedby the patient. Synchronization occurs naturally and has beenconsistently observed to occur in patients with ALS who exhibitvolitional breathing who have been implanted with a DPS. The time ofsynchronization can be predicted or estimated from studies that monitorthe diaphragm EMG and determine when innate activity is consistentlysynchronized with DPS. Alternatively, the stimulation can be presentedfollowing the detection of innate breathing activity. Step 10 refers toa decision point which requires an affirmative response before moving onto Step 11. In the absence of synchronization, Step 9 continues.

Step 11 (FIG. 1B) relates to activity that occurs after synchronizationhas been achieved, when the stimulus intensity can be ramped up to afunctional level to ventilate the patient. Alternatively, if thediaphragm EMG is detected for synchronization, the absence of activitycan cause the stimulus intensity to elicit a functional contraction.Absence of activity can be predetermined as a time equivalent to thedefinition of an apneic event (i.e. 10 seconds) or a time based on theperiodicity of prior breathing.

As described above, parameters that are individually adapted to thepatient during an early phase of the method 202 (FIG. 1A) generallyallow a comfortable merging of electrically-paced breathing into anatural course of sleep onset and continuing through the sleep cycle ofa patient who is not on full time pacing. One feature of the method thatallows this comfortable merger is the delay in onset of the pacing untilan appropriate time after the patient has begun to sleep. Thus, in someembodiments of the method, the stimulation protocol includes an onsetdelay period before the onset of stimulation (e.g., approximately 5minutes, 10 minutes, 20 minutes, 30 minutes, etc.).

Another feature of the method that supports merging of the patient'snormal breathing with paced breathing during sleep includes ramping ofstimulation of the patient's diaphragm to support breathing, as itoccurs at various phases of the method. The role of ramping is at leasttwo-fold. In one aspect, ramping serves the purpose of not interruptingor disturbing the onset of sleep. In another aspect, stimulation levelramping serves to allow a synchronization of the patient's own breathingrate to the rate being driven by pacing stimulation. Ramping theelectrical stimulation of the diaphragm may occur in various forms, suchas increasing pulse duration and then increasing pulse amplitude,increasing pulse amplitude and then increasing pulse duration, orincreasing pulse amplitude and pulse duration in an interleaved manner.With regard to the general form of the ramping, ramping may occur with alinear envelope, with an exponential envelope, or with an envelope of anarbitrary or irregular shape.

Embodiments of the method for improving sleep disordered breathing maybe implemented by a system 10 which will be described first in generalteems, as shown in FIG. 2A, and then depicted (FIG. 2B) and described inmore detail below. Embodiments of the system 10 typically includevarious primary subsystems. One subsystem is represented by an apparatusor assembly of components that act as an electronic signal stimulator ordiaphragm pacing system (DPS) 110 (including components surrounded by adotted line) that provides electrode-delivered stimulation to thediaphragm of a patient to regulate the patient's breathing. An exampleor typical embodiment of apparatus 110 is provided by the NeuRx DPS™System (Synapse Biomedical, Inc. of Oberlin, Ohio), which includeselectrodes to deliver the stimulation to the target, a stimulationdevice to generate charge balanced waveforms, a microprocessor to formatand coordinate stimulus delivery, and various peripheral components thatembody the device. The output 120 of the electric signal generator 110is directed to electrodes implanted in the diaphragm of the patient,which control the breathing rate.

A sleep sequencer processor 130 represents another subsystem, which maybe a separate device or a component incorporated into the main apparatusof the DPS System that includes the electronic signal generator,provides the appropriate cyclic timing to ramp between the thresholdsidentified in the method as shown in FIG. 1B. The sleep sequencer 130may use observation- or experience-based settings or a user adjustableinput to determine the timing of the onset of sleep. Sequencing from thesensory threshold to the movement threshold may be accomplished byproviding the appropriate cyclic timing to ramp stimulation based on aexperience-based setting, or it may use the detection ofelectromyographic diaphragm activity in the contralateral diaphragm upondelivery of stimulation and an absence of electromyographic activitywithout stimulation to sense if the innate breathing has synchronizedwith the stimulation. Finally, the sleep sequencer may ramp stimulationup to the functional threshold to elicit functional contractions toventilate the patient. The functional contraction may be set to the samestimulation level as the movement threshold. Alternatively, once thesensory threshold is achieved, the sleep sequencer may be set to deliverfunctional stimulation in the absence of electromyographic activity wheninspiration should be occurring, i.e. during a central apneic event.

Representing still another component subsystem, the system may alsoinclude electromyographic activity sensing component 140 which receivesdiaphragm EMG activity data from the electrodes implanted in the patientdiaphragm. This electromyographic activity may be processed anddisplayed for manual use in manual operation of the system in amonitored clinical setting or EMG data may be fed into the DPS System orsleep sequencer to automate the apparatus. In a monitored clinicalsetting the absence of diaphragm activity, when inspiration should beoccurring (e.g. within 10 second of the last recorded activity), couldbe used as a diagnostic tool and be coupled with the furtherintervention of application of the diaphragm stimulation.

Features of the system described above in general terms will now bedescribed in greater detail with reference to FIG. 2B, and in a mannerthat tracks the flow of electrical signals. In one embodiment, theelectrical signal generator 110 shown may be configured to generatepulses and/or signals that may take the form of sinusoidal, stepped,trapezoidal waveforms or other relatively continuous signals. Theelectric signal generator 110 may include one or more channels that canindependently control the amplitude, frequency, timing and pulse widthof the corresponding electrodes connected thereto. In one embodiment,the electrical signal generator 110 can be an external signal generatorthat is electrically connected to or in electrical communication withthe electrodes. Example of a suitable electrical signal generatorinclude a NeuRx RA/4 stimulator of the NeuRx DPS™ System (SynapseBiomedical, Inc. of Oberlin, Ohio), which are four-channel devices withindependent parameter programmability, that can, accordinglyindependently control up to four electrodes. In an alternativeembodiment, the electrical signal generator 110 can be an implantablesignal generator. One suitable example of a fully implanted signalgenerator is the “Precision” electrical signal generator available fromBoston Scientific/Advanced Bionics. One example of a partially implantedradio-frequency signal generator system is the “XTREL” system availablefrom Medtronic, Inc.

The electrical signal generator 110 depicted in FIGS. 2A and 2B iscomprised of several blocks to produce a coordinated stimulus output.The core of the electrical signal generator 110 is a supervisorymicrocontroller 111 that coordinates parameter and sensed inputs,display, and stimulus/trigger outputs. The stimulus and timingparameters are stored in non-volatile memory and are programmedspecifically for the respiratory support needs and desired electrodefeatures for the particular patient. A waveform generator 112 assemblesthe control signals from the microcontroller in the necessary waveformpatterns to be conveyed through the output stage signal drivers 113. Themicrocontroller 111 receives power from a power supply 114. It receivesinput of sensing information 115, impedance detection 116, timingparameters 118 and stimulation parameters 150 and EMG data 142, all byway of a sleep sequencer 130. The microcontroller 111 provides output toa trigger output 119 and an LCD 121, in addition to the waveformgenerator 112. The output stage comprising drivers 113 also provideoutput to the impedance detector 116. The drivers 113 provide output inthe form of stimulation of the electrodes 120.

With further reference and in greater detail regarding the sleepsequencer 130, electromyographic signals from electrodes 120 implantedin the diaphragm are collected and conveyed to an electromyographicprocessor 140. The processor 140, in turn, can both display resultingEMG data (available for clinical review by a health care professional)and transmit data to a sleep sequencer 130. The sleep sequencer 130 hasalready received stimulation parameter values input 150 that werecollected during an early aspect of the method, when parameteradaptation studies were run on the patient (Steps 2, 3, and 4 of FIG.1B). The sleep sequencer further receives input 188 regardingrespiratory timing parameters, which may include a manually adjustabletiming input 132. The sleep sequencer thus integrates informationregarding the parameter adaptations, stimulus level ramping, respiratorytiming, and EMG feedback from the diaphragm while it is being paced bythe electrical signal generator assembly. (It may be appreciated thatthese feedback data do not include EMG data from the diaphragm that areassociated with independent breathing effort.) Further, it can beappreciated that input regarding the stimulation parameters 150 and therespiratory timing parameters 118 can be adjusted or revised during thetherapeutic regime, based on changes in the status of the patient andobservation. These data are integrated by the sleep sequence 130 andconveyed to the microcontroller 111.

In some embodiments, the output of drivers 113 is a capacitively-coupledcurrent-regulated biphasic waveform. With each stimulus output, thecircuit impedance is detected and fed back to the microcontroller todisplay electrode circuit integrity. The microcontroller may be drivento send the control signals to the waveform generator from an externalsensed source (either a digital level or analog signal, such asdiaphragm EMG) or from internal timing that is based on the storedtiming parameters. The microcontroller may also be programmed to sendout an analog or digital trigger signal to an external device based on aprogrammed sequence or event.

In one example, the electrical signal generator can supply theimplantable electrodes with an electrical signal that serves aselectrical stimulation to the respiratory system of the patient. Forexample, the electrical signal can be a capacitively-coupled, chargebalanced, biphasic, constant current waveform with adjustable parametersas shown below in Table 1. It will be appreciated that the electricalsignal can take the form of other waveforms for electrical stimulationsuch as monophasic or rectangular biphasic.

TABLE 1 Parameter Range Stimulation Interleave Rate 1-100 Trigger Delay(from inspiration) 1.0-4.0 s Stimulation Time 0.8-1.5 s Output PulsePeriod 20-250 ms Pulse Width Modulation Count 0-10 Cathodic CurrentAmplitude 5-25 mA Cathodic Current Pulse Width 20-200 μs Voltage 0-65 VPulse Frequency 10-20 Hz

Although the stimulatory signal can be delivered to a variety oflocations in the body of a patient to stimulate the respiratory system,in one example, the electrical stimulatory can be delivered to thediaphragm of the patient, through the electrodes, continuously orperiodically, as the patient is falling off to sleep and during sleep.For example, the electrical stimulation can be delivered to thediaphragm of the patient at specified intervals, for a certain period oftime per interval. In typical embodiments of the method, the stimulationis delivered constantly, albeit at rates and intensity that vary betweenthe initial phase of sleep and the stable portion of sleep.

The external electrical stimulator makes use of one or moreintramuscular electrodes that are suitable for implanting into muscletissue. In some embodiments, the intramuscular electrode can serve as acathode. In some embodiments, the electrode is particularly adapted fortemporary implantation. Examples of appropriate electrodes and theirfeatures are described in detail in U.S. patent application Ser. No.11/716,459 of Ignagni, entitled “Ventilatory assist system and methodsto improve respiratory function”, as filed on Mar. 9, 2007, now U.S.Pat. No. 7,962,215, which is incorporated herein in its entirety by thisreference.

The inventive system and method have been developed and tested onpatients under appropriate protocols and safety guidelines. FIGS. 3-5provide examples of the human subject data that have been collected.Exemplary electromyographic recordings are shown in FIGS. 3A and 3B thatwere obtained from an ALS patient that had been implanted with pacingelectrodes 18 months prior to the time these recordings were made. Thetwo sets of traces show the electromyographic recording from right andleft hemi-diaphragms. (There is a difference between the right and theleft traces that is a result of differences in placement; thatdifference does not distract from the significance of the data as theyrelate to reflecting EMG activity.) In FIG. 3A a depressed, low level,electromyographic recording is shown during a period of normal awakebreathing. In FIG. 3B a significant increase in the magnitude of theelectromyographic recording is shown during a period of maximallyvolitional breathing. This demonstrates the ability of the system todetect electrode myographic activity and to differentiate the amountdiaphragm movement based on magnitude of electromyographic recordings.An absence of activity or a minimal of activity may be used to asdiagnostic criteria or feedback indicating an insufficient diaphragmcontraction.

An exemplary episodic view of sleep disordered breathing in an ALSpatient, exhibiting deficits in upper motor neuron function is shown inFIGS. 4A and 4B. The upper panel (FIG. 4A) shows a Cheyne-Stokes typebreathing pattern with the right and left hemidiaphragms exhibitingapneic events followed by two quick bursts of diaphragm activityfollowed by another apneic event and two quick bursts of diaphragmactivity. The bottom trace of the upper panel (FIG. 4A) shows the pulseoximetry (SPO₂) fluctuating, as expected, following the apneic events.The upper trace of the lower panel (FIG. 4B) shows the patient withoutthe support of DPS demonstrating respiratory instability as evidenced bythe ongoing oscillation of the pulse oximetry. The patient showsresolution of the respiratory instability with the addition of DPS, inthe bottom trace.

An example of processing electromyographic activity of an ALS patient isshown in FIGS. 5A and 5B. In this case, the sampled electromyographicactivity was processed by filtering to remove the undesired EKG signal,rectified, and then an average magnitude of the signal amplitude wascalculated. Data were collected at two time points 11 weeks apart (FIG.5A at the outset of the study, FIG. 5B after 11 weeks of therapy). Inthe example shown, the electromyographic activity is seen to increaseover time with conditioning of the diaphragm in a patient experiencingrespiratory insufficiency. These EMG data correlated well withfluoroscopy data showing diaphragm movement. Similarly the amplitude ofthe activity can be used to discriminate a functional contraction from anon-functional contraction.

In another example, a clinical study was run to evaluate the effect ofdiaphragm pacing treatment, in accordance with the inventive method, onpatients with neuromuscular disease who had disordered sleep patternsand disordered breathing during sleep. The results of the study suggestthat benefits may derive from the treatment; accordingly, some generalobservations and considerations will be described, and some relevantdata will be provided below.

Patients that cannot readily tolerate non-invasive positive pressureventilation (NIPPV) may be particularly benefited by the methods andsystems described herein. Considerations that particularly recommend theuse of this inventive therapeutic method for these patients areindications that NIPPV may actually accelerate the deconditioning of thediaphragm and the dependence of ALS patient on increasing amounts ofNIPPV (Aboussouan, et al., “Effect of noninvasive positive pressureventilation on survival in amyotrophic lateral sclerosis”. Ann InternMed 1997; 127: 450-453). The trade off between the benefit of immediateassistance in breathing against the acceleration the disease progressionis, of course, very undesirable. Combining diaphragm pacing stimulation(DPS) therapy with NIPPV may slow or eliminate this nocturnaldeconditioning of the diaphragm, and further slow the patient'sprogression toward complete dependence on NIPPV support. Beforeimplementation of diaphragm pacing stimulation, particularly duringsleep, various operational parameter settings for diaphragm pacingstimulation that provide a level of respiratory assistance withoutarousing the patient from sleep may be determined.

Embodiments of the DPS method, as provided herein, typically involve theimplanting of a DPS device and an extended period of DPS therapy. Thediaphragm pacing stimulation includes sufficient stimulation to initiatea breath and further stimulation sufficient to support a breath tocompletion. As described herein, the method may be adapted for thetherapeutic application of improving the quality of sleep, and may befurther adapted to the physiological and temperamental particulars ofeach patient (Steps 2-4 of FIG. 1). These adaptations for diaphragmpacing during sleep may include, for example, any one or more of a delayof stimulation onset to allow patient to fall asleep, a gradual rampingof diaphragm stimulation level over time after onset of stimulation,setting a steady state level of stimulation so as to minimize arousalfrom sleep, and the monitoring of diaphragm EMG during system use.

A programmable delay in the onset of stimulation, merely by way ofexample, may be set for an interim of 15 seconds to 30 seconds afterinitiation of sleep. A ramping period after initiation of electrodestimulation may be, merely by way of example, of about 30 minutes,wherein a minimal stimulation is provided at the outset, and a plateaulevel of stimulation is reached at 30 minutes, and such plateau level iscontinued through the sleep period. Further, a sleep-appropriate plateaulevel of respiration may be set that permits sleep without awakening,such level, as driven by diaphragm pacing may be set, merely by way ofexample, within a range of about 8 to 20 respirations per minute.

Additionally, the stimulus frequency may be set such that the deliveredstimulation is at a level to produce fused contractions of the diaphragmmuscle. The fusing of contractions in a diaphragm, which is composedprimarily of slow twitch type JIB muscle fiber, will exhibit unfusedcontraction at a low frequency. A threshold level of stimulation isrequired to elicit a desirable and sustainable fused contraction.Accordingly, the frequency may be ramped up over the initiation periodto produce a more forceful contraction while remaining below a levelthat would cause the patient to awake. Increases in delivered stimulusmay be performed based on the charge (the product of pulse duration andamplitude) delivered on a pulse-by-pulse basis. By initiating eachinspiration with a very gradual ramping, the stimulus may be deliveredslowly, and then increased with a steeper ramp to create a greaterinspiratory pressure and thus greater volume for each breath. Followinga determination and setting of stimulation parameters that have beenadapted or optimized for sleep, a therapeutic regimen of diaphragmstimulation may be implemented.

The implanted DPS electrodes may be used to record diaphragm EMG duringthe polysomnographic recording, or they may be used in a stand alonemanner to determine the amount of diaphragm activation during adiagnostic sleep session. In either context, the EMG data may provide aphysician with information that allows an evaluation of the diseasestate and the efficacy of the diaphragm pacing in improving sleep. Insome embodiments of the method, the parameters that have been adapted tomake the diaphragm pacing stimulation appropriate for sleep may beevaluated by a physician and revised in accordance with accumulated EMGdata, or any other relevant clinical data. Following such revision ofparameters adapted for stimulation of the diaphragm during sleep, arevised therapeutic regimen may be implemented.

It can be noted that although it may be technically feasible to includea feedback loop in the method, whereby patient initiated breathingeffort during sleep would be incorporated into the control of breathingby DPS. In the view of the inventors, however, this approach appearsdisadvantageous for several reasons, including the complexity and likelytemperamental or unstable nature of such a method that included suchfeedback, the associated burden of training physicians in the method,and the cost of the system. On the whole, inventors believe that asystem that operates under the discretionary control of healthprofessionals exercising clinical judgment with an open loopimplementation (instead of the automatic control of a voluntaryrespiratory effort feedback loop) offers an approach that makes themethod safe, robust, and effective. Accordingly, a feedback loop thatincorporates patient-initiated breathing effort data as feedback intothe system control is not included in the inventive method.

In the clinical study referred to above, twelve of the 16 ALS patientshad bulbar symptoms, such symptoms being consistent with poor toleranceof noninvasive positive pressure ventilation therapy. At the time ofimplant of the DPS device, the patients had a median forced vitalcapacity (FVC) of 57% of the predicted value, and a median score of 26on the ALS Functional Rating Scale-revised (ALSFRS-R). The studypatients have a mean survival from diagnosis of 3.0±0.7 years. Fromreports in the literature (Louwerse, et al., “Amyotrophic lateralsclerosis: morality risk during the course of the disease and prognosticfactors”. Publications of the Universiteit van Amsterdam, Netherlands.1997), the median survival time from diagnosis was 1.4 years (95%confidence interval, 1.3-1.6 years).

This clinical study also yielded observations that indicate that ALSpatients may be more tolerant of DPS than NIPPV, and that they can makeuse of the DPS stimulation for extended periods to improve theirbreathing, which may improve the quality of their sleep. A few ofpatients in the pilot study voluntarily switched from BiPAP therapy toDPS because of their perception of greater ease in breathing. Forexample, some patients have fallen asleep while using the DPS system andreported that they then slept better than they had in some time.

Another measure of outcomes in ALS is provided by the revised FunctionalRating Scale (ALSFRS-r). This is a disease-specific scale that measuresglobal function as grouped around several elements such as limbfunction, bulbar function, and respiratory function. The slope of ALSFRSover time has a greater correlation with survival than does the slope offorced vital capacity. In a large retrospective clinical study theeffects of Neurontin, it was found that three groups of patients couldbe classified by the rate of progression of their ALSFRS-r score. Slowlyprogressing patients (patients with a rate of decline less than −0.44ALSFRS units per month) had median survival of more than 3 years,moderately progressing patients (patients with a rate of decline between−1.04 and −0.44) had a median survival of 2.3 years, and rapidlyprogressing patients (patients with a rate of decline greater than−1.04) had a median survival of 1.3 years. Performing a pairedcomparison of the rate of decline of patients in the DPS clinical studyperformed by the inventors yields an average survival improvement of 9months (p=0.03).

As the diaphragm is the principal (or sole) respiratory muscle activeduring REM sleep, reduced or lost function of this muscle leads to sleepirregularities with fragmentation by multiple arousals and awakenings.Polysomnographic recordings of sleep with and without rhythmic diaphragmpacing stimulation demonstrate this effect. Overnight EMG recordings ofthe diaphragm with nocturnal pulse oximetry in ALS patients implantedwith the NeuRx DPS™ System demonstrate that low levels of blood oxygenare associated with depressed diaphragm contraction.

It should also be understood that this therapeutic method may be appliedin patients who are being treated more generally for ALS andhypoventilation, and with goals directed toward improving ventilationand the quality of life. Accordingly, for example, a primary efficacyendpoint of improvement in breathlessness may be measured using theModified BORG Scale. This unidimensional, health related, quality oflife instrument provides a recognized, reproducible measure of physicaleffort, and more specifically in this context, the intensity of thesensation of breathing effort or breathlessness. Measurements can bemade, as the patient is able, without support (i.e., without NIPPV orDPS) and in combinations of support. These measurements can be recordedprior to implantation of the DPS electrodes for baseline data, and thenat regular intervals following the initiation of DPS treatment. Otherendpoints include the daily use of DPS and NIPPV, as patients willrecord categorized hours used of each therapy and the weekly preferencefor ventilation therapy on the log form. Finally, a measure of nocturnalhypoventilation can be performed at regular week intervals by recordingthe nighttime SpO₂ with a software-driven recording system such asCrystal PSG™ device. The nocturnal oxygen desaturation index (ODI) andthe % of monitoring time spent in hypoxia (SpO2<90%) pre-implant andpost-implant can be calculated. The ODI represents the number of timesper hour of monitoring that the SpO2 desaturates by more than 4%.Measurements of breathlessness and ODI can be made under consistentconditions with respect to the patients' use of supplemental oxygen andwill be made with and without DPS.

In addition to ALS patients, other types of patients could benefit fromDPS supported breathing during sleep. Any patient, for example, withupper motor neuron dysfunction, even in conjunction with lower motorneuron dysfunction that results in temporary or permanent diaphragmparalysis is an appropriate candidate for DPS therapy. Periodicrespiratory instability, as demonstrated in patients with central sleepapnea and congestive heart failure are prime candidates for DPSintervention. Other examples of diaphragm paralysis have been reportedin patients with Charcot-Marie-Tooth disease, associated with diabetesmellitus, spinal cord injury, poliomyelitis, Guillain-Barre' syndrome,diabetes, diphtheric neuropathy, beriberi, alcoholic neuropathy,brachial plexus neuropathy, lead neuropathy, trauma, myotonic dystrophy,Duchenne's muscular dystrophy, paraneoplastic syndrome, and idiopathicconditions.

By way of further examples, post surgical patients that are at risk ofmechanical ventilation in the intensive care unit (ICU) may benefit frommonitoring and intervention. An example of an at-risk surgicalpopulation would include bariatric patients. These patients, because oftheir obesity are already prone to sleep dysfunction and often havedifficulty with the recovery and regulation of CO₂ as a result of alaparoscopic surgical procedure for their obesity. An evaluation periodaccording to Steps 2-4 of the method (FIG. 1) may appropriately beperformed prior to surgery in order to obtain patient specific parametervalues. A typical bariatric procedure involves work at or around thediaphragm, and thus could easily include placement of intramuscularelectrodes in the diaphragm for subsequent monitoring of diaphragm EMGactivity during recovery. If sporadic diaphragm contraction is observedby ICU staff, then rhythmic diaphragm contraction would be commenced toavoid apneas and potential intubation for the patient. Stimulation wouldthen proceed throughout the night, until the patient awakens anddiaphragm respiration can be supplemented with intercostal and accessorymuscle respiration under volitional control centers of the patient.

Unless defined otherwise, all technical terms used herein have the samemeanings as commonly understood by one of ordinary skill in the art towhich this invention belongs. Specific methods, devices, and materialsare described in this application, but any methods and materials similaror equivalent to those described herein can be used in the practice ofthe present invention. While embodiments of the inventive device andmethod have been described in some detail and by way of exemplaryillustrations, such illustration is for purposes of clarity ofunderstanding only, and is not intended to be limiting. Various termshave been used in the description to convey an understanding of theinvention; it will be understood that the meaning of these various termsextends to common linguistic or grammatical variations or forms thereof.It will also be understood that when terminology referring to devices orequipment has used trade names, brand names, or common names, that thesenames are provided as contemporary examples, and the invention is notlimited by such literal scope. Terminology that is introduced at a laterdate that may be reasonably understood as a derivative of a contemporaryterm or designating of a subset of objects embraced by a contemporaryterm will be understood as having been described by the now contemporaryterminology. Further, while some theoretical considerations have beenadvanced in furtherance of providing an understanding, for example, ofways that embodiments of the invention beneficially intervene in thephysiology of muscles and neural pathways responsible for breathing, andthe role of this physiology in sleep, the claims to the invention arenot bound by such theory. Moreover, any one or more features of anyembodiment of the invention can be combined with any one or more otherfeatures of any other embodiment of the invention, without departingfrom the scope of the invention. Still further, it should be understoodthat the invention is not limited to the embodiments that have been setforth for purposes of exemplification, but is to be defined only by afair reading of claims that are appended to the patent application,including the full range of equivalency to which each element thereof isentitled.

What is claimed is:
 1. A method to entrain breathing in a patient, themethod comprising repetitively applying low-levels of physiologicallynormal stimulation to establish a baseline automatic function, whereinthe low-levels of physiologically normal stimulation are applied belowthe patient's movement and sensory threshold to establish an automaticbaseline pacing level while the patient is asleep.
 2. The method ofclaim 1, further comprising implanting one or more electrodes in thepatient's diaphragm, wherein the low-levels of physiologically normalstimulation are applied through the one or more electrodes.
 3. Themethod of claim 2, wherein the one or more electrodes are configured forpermanent placement in the patient's diaphragm.
 4. The method of claim2, wherein the one or more electrodes are configured for temporaryplacement in the patient's diaphragm.
 5. The method of claim 1, whereinthe patient is suffering from daytime hypoventilation.
 6. The method ofclaim 1, wherein the patient is suffering from temporarily compromisedbreathing.
 7. The method of claim 6, wherein the temporarily compromisedbreathing is the result of respiratory arrest.
 8. The method of claim 1,wherein the low-levels of physiologically normal stimulation are appliedwhile the patient is sleeping.
 9. The method of claim 1, furthercomprising stimulating the patient's diaphragm above the movementthreshold while the patient is asleep after the automatic baselinepacing level is established.
 10. The method of claim 9, furthercomprising stimulating the patient's diaphragm while the patient isawake to establish an automatic breathing mechanism.
 11. The method ofclaim 10, further comprising evaluating the patient's diaphragm by EMGto determine the effectiveness of the establishment of the automaticbreathing mechanism.
 12. A method of entraining breathing in a patient,the method comprising: identifying a patient suffering from or at riskof daytime hypoventilation; stimulating the patient's diaphragm byapplying stimulation below the patient's movement and sensory thresholdto establish an automatic baseline pacing level; stimulating thepatient's diaphragm by applying stimulation above the patient's movementthreshold after the automatic baseline pacing level has beenestablished; and establishing an automatic breathing mechanism.
 13. Themethod of claim 12, wherein the stimulation below the patient's movementand sensory threshold is applied while the patient is sleeping.
 14. Themethod of claim 12, wherein the stimulation above the patient's movementthreshold is applied while the patient is sleeping.
 15. A method ofentraining breathing in a patient, the method comprising: stimulatingthe patient's diaphragm while the patient is asleep by applyingstimulation below the patient's movement and sensory threshold toestablish an automatic baseline pacing level; stimulating the patient'sdiaphragm while the patient is asleep by applying stimulation above thepatient's movement threshold after the automatic baseline pacing levelhas been established; and establishing an automatic breathing mechanism.16. The method of claim 15, further comprising stimulating the patient'sdiaphragm while the patient is awake by applying stimulation above thepatient's movement threshold after the automatic baseline pacing levelhas been established.